Metabolic Imaging of Brain Tumor Response to Therapy

脑肿瘤治疗反应的代谢成像

• 批准号: 9249001
• 负责人: Sabrina Miriam Ronen
• 金额: $ 63.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249001
• 关键词: 6-phosphogluconate; Affect; Aftercare; Age; Asses; Biochemical; Biological Assay; Biological Markers; Brain Neoplasms; Caring; Cells; Cessation of life; Citric Acid Cycle; Clinical Trials; Communities; Data; Diagnosis; Drug Targeting; Drug effect disorder; Edema; Enhancing Lesion; Gadolinium; Gene Expression; Glioblastoma; Glioma; Glucose; Glutamates; Glutamine; Goals; Growth; Image; Isocitrate Dehydrogenase; Lead; Link; Liquid substance; Magnetic Resonance; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of brain; Metabolic; Modeling; Monitor; Mus; Mutation; Newly Diagnosed; Oligodendroglioma-Astrocytoma; Oligonucleotides; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pentosephosphate Pathway; Population; Production; Pyruvate; Recovery; Recurrent tumor; Research; Role; T2 weighted imaging; Treatment Efficacy; Tumor Markers; attenuation; base; cancer imaging; cancer type; imaging approach; imaging biomarker; imaging modality; improved; in vivo; inhibitor/antagonist; lactate dehydrogenase A; magnetic resonance spectroscopic imaging; metabolic imaging; neuro-oncology; novel; novel strategies; oligodendroglioma; precision medicine; predicting response; predictive marker; public health relevance; response; response biomarker; temozolomide; treatment effect; treatment response; tumor; years of life lost

 DESCRIPTION (provided by applicant): Gliomas result in more years of life lost than any other cancer type. GBM is the most aggressive form of glioma, whereas oligodendroglioma (oligo) and astrocytoma (astro) tumors are characterized by a slower growth rate and longer survival. However, they affect a younger population and, because they are highly invasive, almost uniformly result in patient death. There is therefore an increasing focus on more aggressive treatments for oligo and astro patients. In particular, temozolomide (TMZ) and PI3K pathway inhibitors (PI3Kis) are currently in clinical trials. However, imaging of oligo and astro tumors and monitoring their response to therapy can be challenging, and new approaches are needed. The goal of this study is to identify and mechanistically validate magnetic resonance spectroscopy (MRS) - based metabolic imaging biomarkers of oligo and astro response to therapy. Our preliminary MRS data indicate that treatment with TMZ or PI3Kis leads to modulation of tricarboxylic acid (TCA) cycle flux and intracellular glutamate and glutamine levels but does not affect lactate production, consistent with gene expression data indicating a central role for the TCA cycle, but not for lactate synthesis, in oligos and astros. In addition, our preliminary data show that in TMZ-treated cells 6-phosphogluconate levels produced from hyperpolarized glucose are elevated, indicating an increase in flux towards the pentose phosphate pathway. We therefore hypothesize that metabolic imaging of the TCA cycle and pentose phosphate pathway can serve to inform on oligo and astro response to therapy. Based on this hypothesis we propose to investigate unique recently developed genetically characterized patient-derived oligo and astro models, and to develop new MRS biomarkers of response to treatment via the following Aims. Aim 1. To identify 1H and HP 13C MRS biomarkers of oligodendroglioma and astrocytoma response to therapy in neurosphere models. We will investigate control and treated oligo and astro neurospheres, as well as GBM neurospheres, and use 1H and HP 13C MRS to identify metabolic alterations that inform on oligo and astro response to TMZ or PI3Kis. Aim 2. To determine the translational value of 1H and HP 13C MRS biomarkers by monitoring therapeutic response in orthotopic tumors in vivo. We will investigate control and treated oligo and astro tumor-bearing mice and determine the value of 1H and HP 13C MRS biomarkers identified in Aim 1 to inform on drug-target engagement and predict response to therapy with TMZ or PI3Kis. Aim 3. To validate the metabolic biomarkers by mechanistically linking metabolic findings with drug action. We will investigate neurospheres from Aim 1 and excised tumors from Aim 2 and use biochemical and cell biological assays to validate our imaging biomarkers by determining the underlying mechanism for their modulation by treatment.

 描述（由申请人提供）：与任何其他癌症类型相比，胶质瘤导致的寿命损失更多年，GBM 是最具侵袭性的胶质瘤形式，而少突神经胶质瘤 (oligo) 和星形细胞瘤 (astro) 肿瘤的特点是生长速度较慢且时间较长。然而，它们影响较年轻的人群，并且由于它们具有高度侵入性，几乎都会导致患者死亡，因此人们越来越关注对寡核苷酸和 astro 患者的更积极的治疗。替莫唑胺 (TMZ) 和 PI3K 通路抑制剂 (PI3Kis) 目前正在进行临床试验，然而，寡聚肿瘤和星形肿瘤的成像以及监测其对治疗的反应可能具有挑战性，因此需要新的方法来识别和治疗。从机制上验证基于磁共振波谱 (MRS) 的寡核苷酸和 astro 对治疗反应的代谢成像生物标志物。我们的初步 MRS 数据表明，TMZ 或 PI3Kis 治疗会导致调节。三羧酸（TCA）循环通量和细胞内谷氨酸和谷氨酰胺水平，但不影响乳酸产生，这与基因表达数据一致，表明TCA循环在oligos和astros中发挥核心作用，但不影响乳酸合成。此外，我们的初步研究。数据显示，在 TMZ 处理的细胞中，超极化葡萄糖产生的 6-磷酸葡萄糖酸水平升高，表明戊糖磷酸途径的通量增加，因此我们捕获了该代谢成像。 TCA 循环和磷酸戊糖途径的研究可以帮助了解寡核苷酸和 astro 对治疗的反应。基于这一假设，我们建议研究最近开发的独特的遗传特征的患者衍生寡核苷酸和 astro 模型，并开发新的 MRS 响应生物标志物。通过以下目标进行治疗 目标 1. 确定少突胶质细胞瘤和星形细胞瘤对神经球模型治疗的反应的 1H 和 HP 13C MRS 生物标志物。目标 2. 通过监测治疗反应来确定 1H 和 HP 13C MRS 生物标志物的翻译价值。我们将研究对照和治疗的oligo和astro荷瘤小鼠并确定1H和HP的值。目标 1 中确定的 13C MRS 生物标志物可告知药物靶点参与情况并预测对 TMZ 或 PI3Kis 治疗的反应。目标 3：通过将代谢结果与药物作用机制联系起来来验证代谢生物标志物。我们将研究来自目标 1 和切除的神经球。来自 Aim 2 的肿瘤，并使用生化和细胞生物学检测通过确定治疗调节的潜在机制来验证我们的成像生物标志物。